The primary goal of this Program Project Grant renewal is to identify the neurobiological mechanisms that underlie the pathophysiology and treatment of depression. A major strength of this application is the integrated and multi-disciplinary approach, including molecular, biochemical, electrophysiological, and behavioral levels of analysis for each research project. Another strength is the close interaction between the basic and clinical research faculty that allows for efficient and productive transfer of information. This program of research consists of a small Administrative ore, two scientific Cores, and 4 research projects. The Molecular and Transgenic Core is responsible for the breeding and development of mutant mice and for viral vectors that are used to investigate molecular models in the 4 research projects. The Behavioral Core is responsible for testing rodents in standard models of depression and anxiety. This Core is used by the 4 research projects to determine the behavioral phenotype of mutant mice, effects of viral-mediated gene transfer, and responses to systemic and intracerebral drug infusions. Project by Russell will extend our finding that brain derived neurotrophic factor (BDNF) produces an anti- depressant effect in behavioral models of depression This will include molecular, electrophysiological, and behavioral analysis of the intracellular pathways that are regulated by neurotrophic factors in limbic brain regions. Project by Alreja will determine the role of septal pathways in the regulation of hippocampal function by stress and antidepressant treatments, and the molecular, neurochemical, and electrophysiological determinants underlying these effects. Project by Duman is a continuation of our previous studies demonstrating that anti- depressant treatment produces morphological adaptations, most notably increased neurogenesis in adult rodent hippocampus. This project will include the molecular and biochemical analysis of the signal transduction pathways that regulate adult neurogenesis and the behavioral consequences of these effects. Project by Taylor will determine the role of the amygdala and nucleus accumbens and intracellular signaling in these brain regions, in established models of depression and conditioned reward. Funding of this program of research will ensure the continued success of these multidisciplinary studies to identify the molecular and cellular basis of depression, and that could lead to novel therapeutic interventions.